Disturbances in the hypothalamic-pituitary-thyroid axis (HPT) may have an etiologic role in patients with rapid-cycling manic-depressive illness. These patients are more likely to develop lithium-induced hypothyroidism and in open clinical trials their mood fluctuations may improve when treated with hypermetabolic doses of thyroxine. The purpose of our present study is to define the nature of the HPT abnormality in these patients to assess in a double blind, placebo controlled trial whether thyroxine is an effective treatment in these patients. As part of ongoing research we have studied the therapeutic effects of euthyroid and hypermetabolic doses of thyroxine in six patients with a history of rapid-cycling manic-depressive illness. Of the six, five completed the study. All subjects were treated with euthyroid and hypermetabolic doses of thyroxine. Two patients with extremely short cycles (6-8 days) remitted when treated with hypermetabolic doses and relapsed when their dose of thyroxine was decreased. Of the other three patients, two were antidepressant-induced cyclers, who were depressed but not cycling at the time of the study. Neither of these patients showed any improvement. Our preliminary results suggest that: 1) hypermetabolic but not euthyroid treatment with thyroxine may be effective in treating rapid cyclers 2) patients with very short cycles which are not drug-induced are most likely to benefit from this treatment.